Post-SSRI sexual dysfunction
Post-SSRI sexual dysfunction (PSSD)Bahrick AS (2006). “Post SSRI Sexual Dysfunction” (PDF). Tablet 7 (3): 2-10. is a name given to a reported iatrogenic sexual dysfunction caused by the previous use of selective serotonin reuptake inhibitor (SSRI) antidepressants. While apparently uncommon, it can last for months or years after the discontinuation of SSRIs.Csoka AB, Bahrick AS, Mehtonen O-P (2008). “Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs)”. J Sex Med 5 (1): 227-33 doi:10.1111/j.1743-6109-2007-00630.x. PMID 18173768. It may represent a specific subtype of Wikipedia:SSRI discontinuation syndrome. This condition has not been well-established or studied in the field of medicine. See also Wikipedia:Articles for deletion/Post-Finasteride Syndrome and the page history of Wikipedia:Isotretinoin Symptoms One or more of the following sexual symptoms attributed to PSSD after the discontinuation of SSRIs include: * Decreased libido * Impotence or reduced vaginal lubrication * Difficulty initiating or maintaining an erection or becoming aroused * Persistent genital arousal disorder (PGAD) despite absence of desire * Muted, delayed or absent orgasm (anorgasmia) * Reduced or no experience of pleasure during orgasm (ejaculatory anhedonia) * Premature ejaculation * Weakened penile, vaginal or clitoral sensitivity * Genital anaesthesia * Loss or decreased response to sexual stimuli Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors J Sex Med 2008;5:227–233 Prevalence The true prevalence of PSSD has yet to be determined, although published calls have been made for post-marketing epidemiological studies. Kauffman RP (2008). “Persistent Sexual Side Effects after Discontinuation of Psychotropic Medications”. Primary Psychiatry 15: 24. Farnsworth KD, Dinsmore WW (January 2009). “Persistent sexual dysfunction in genitourinary medicine clinic attendees induced by selective serotonin reuptake inhibitors”. Int J STD AIDS 20(1): 68–9. doi:10.1258/ijsa.2008.008402 PMID 19103903. It is known that SSRIs can cause various types of sexual dysfunction. Initial studies found that such side effects were reported in less than 10% of patients. When doctors have specifically asked about treatment-emergent sexual difficulties, some have found that they are present in up to 60% of patients. Zajecka J, Mitchell S, Fawcett J (1997). “Treatment-emergent changes in sexual function with selective serotonin reuptake inhibitors as measured with the Rush Sexual Inventory”. Psychopharmacol Bull 33 (4): 755–60. PMID 9493488 Spontaneous reporting methods are believed to result in lower reporting rates than targeted questions, either due to recall bias or stigma regarding sexual dysfunction. Balon R (September 2006). “SSRI-associated sexual dysfunction”. Am J Psychiatry 163 (9): 1504–9; quiz 1664. doi:10.1176/appi.ajp.163.9.1504. PMID 16946173. Study data While sexual dysfunction can be common while taking SSRIs, the problem of persistent dysfunction after discontinuation does not appear to be as frequent, or at least not as well-known. Bahrick AS (2008). “Persistence of Sexual Dysfunction Side Effects after Discontinuation of Antidepressant Medications: Emerging Evidence”. The Open Psychology Journal 1: 42–50 doi:10.2174/1874350100801010042. Onset of sexual problems often occurs during, and sometimes after, extended SSRI use but there have been reports of rapid onset as well. Some people do not regain their sexual function after stopping SSRIs, and are faced with the persistent symptoms of post-SSRI sexual dysfunction (PSSD). In one study in which patients with SSRI-induced sexual dysfunction were switched to the dopaminergic antidepressant amineptine, 55% still had at least some type of sexual dysfunction after six months compared to 4% in the control group treated with amineptine alone. Montejo AL, Llorca G, Izquierdo JA, et al. (1999). “Sexual dysfunction with antidepressive agents. Effect of the change to amineptine in patients with sexual dysfunction secondary to SSRI“. Actas Esp Psiquiatr (in Spanish; Castilian) 27 (1): 23–34. PMID 10380144. In recent placebo controlled double-blind studies testing the efficacy of SSRIs for treating premature ejaculation, it has been noted that the ejaculation-delaying effect of the medications may last for months after discontinuation in a percentage of the trial participants. Safarinejad MR, Hosseini SY (2006). “Safety and efficacy of citalopram in the treatment of premature ejaculation: a double-blind placebo-controlled, fixed dose, randomized study”. Int. J. Impot. Res. 18 (2): 164–9. doi:10.1038/sj.ijir.3901384. PMID 16107866. Arafa M, Shamloul R (2006). “Efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire”. Int. J. Impot. Res. 18 (6): 534–8. doi:10.1038/sj.ijir.3901469. PMID 16554853. Safarinejad MR (October 2007). “Safety and efficacy of escitalopram in the treatment of premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study”. J Clin Psychopharmacol 27 (5): 444–50. doi:10.1097/jcp.0b013e31814b98d4. PMID 17873675. Case reports Three cases of hyposexuality following SSRI use Csoka AB, Shipko S (2006). “Persistent sexual side effects after SSRI discontinuation”. Psychother Psychosom 75 (3): 187–8. doi:10.1159/000091777. PMID 16636635. and a fourth case describing genital anesthesia following SSRI use were described in 2006. Bolton JM, Sareen J, Reiss JP (2006). “Genital anaesthesia persisting six years after sertraline discontinuation”. J Sex Marital Ther 32 (4): 327–30. doi:10.1080/00926230600666410. PMID 16709553. A fifth case of similar findings was published in late 2007. Kauffman RP, Murdock A (2007). “Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone”. The Open Women’s Health Journal 1: 1–3. In early 2008, three more cases were published in the Journal of Sexual Medicine, selected from a Yahoo Group composed of over 3500 PSSD sufferers. There have also been several published cases of Persistent Genital Arousal Disorder (PGAD) Goldmeier D, Leiblum SR (April 2006). “Persistent genital arousal in women — a new syndrome entity”. Int J STD AIDS 17 (4): 215–6. doi:10.1258/095646206776253480. PMID 16595040. Goldmeier D, Bell C, Richardson D (March 2006). “Withdrawal of selective serotonin reuptake inhibitors (SSRIs) may cause increased atrial natriuretic peptide (ANP) and persistent sexual arousal in women?”. J Sex Med 3 (2): 376. doi:10.1111/j.1743-6109.2006.00224.x. PMID 16490037. Leiblum SR, Goldmeier D (2008). “Persistent genital arousal disorder in women: case reports of association with anti-depressant usage and withdrawal”. J Sex Marital Ther 34 (2): 150–9. doi:10.1080/00926230701636205. PMID 18224549. and premature ejaculation Adson DE, Kotlyar M (December 2003). “Premature ejaculation associated with citalopram withdrawal”. Ann Pharmacother 37 (12): 1804–6. doi:10.1345/aph.1D214. PMID 14632589. that start and last long after withdrawal from SSRIs. These symptoms are quite different from, and should not be confused with, hypersexuality. Sandra Leiblum described persistent genital arousal disorder based on a case where a PSSD was established. Leiblum, SR; Nathan, S (2001). “Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality”. J Sex Marital Ther. 27 (4): 365–380. Surveillance and reporting To establish, monitor, and regulate causation of PSSD in individual patients, one approach in use by consultation-liaison psychiatrists is to assay measurable parameters of patient health (hormone levels, sexual functioning) with a survey or laboratory tests before and after administering a psychiatric drug, based on individual patient concern regarding each of the listed side effects. If PSSD develops, a correlation can be established between assay results and PSSD, guiding further treatment for the individual patient and others. A lack of education on drug side effects and the presence of clinical depression in a patient who is a candidate for antidepressant therapy can combine to reduce the patient’s ability to advocate for tests. Calls have been made for better informed consent regarding the possibility of permanent sexual dysfunction when prescribing SSRIs to potential patients. Bahrick AS, Harris MM (2008). “Sexual Side Effects of Antidepressant Medications: An Informed Consent Accountability Gap”. Journal Contemp Psychother. Post-administration reporting of side effects may provide useful data for development of new drugs and better inform patients of their risks. In The United States, adverse effects are reported with FDA forms, 3500 for optional use (patients can self-report using this form), and 3500A, for mandatory reporting. Etiology It is currently not known what causes PSSD. Fluoxetine (Prozac), the prototypical SSRI, is classified as a reproductive toxin Hines RN, Adams J, Buck GM, Faber W, Holson JF, Jacobson SW, Keszler M, McMartin K, Segraves RT, Singer LT, Sipes IG, Williams PL. NTP-CERHR Expert panel report on the reproductive and developmental toxicity of fluoxetine. NIH Publication No. 05-4471. 2004;1-211. by the Center for the Evaluation of Risks to Human Reproduction (CERHR), an expert panel at the National Institute of Environmental Health Sciences at the National Institutes of Health. Animal studies Experiments with rodents have shown that chronic treatment with SSRIs at a young age results in permanently decreased sexual behavior that persists into adulthood and is similar to PSSD. Maciag D, Simpson KL, Coppinger D, et al. (January 2006). “Neonatal Antidepressant Exposure has Lasting Effects on Behavior and Serotonin Circuitry”. Neuropsychopharmacology 31 (1): 47–57 doi:10.1038/sj.npp.1300823. PMC 3118509. PMID 16012532. de Jong TR, Snaphaan LJ, Pattij T, et al. (January 2006). “Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats”. Eur Neuropsychopharmacol 16 (1): 39–48. doi:10.1016/j.euroneuro.2005.06.004. PMID 16107310. These studies found reductions in both the rate-limiting serotonin synthetic enzyme, tryptophan hydroxylase, in dorsal raphe and in serotonin transporter (SERT) expression in the cortex. It also appears as though PSSD might be transgenerationally inherited, at least in rodents, since maternal exposure to fluoxetine impairs sexual motivation in adult male mice. Gouvêa TS, Morimoto HK, de Faria MJ, Moreira EG, Gerardin DC (September 2008). “Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice”. Pharmacol. Biochem. Behav. 90 (3): 416–9. doi:10.1016/j.pbb.2008.03.025. PMID 18457868. It is not known whether these findings in rodents recapitulates the human condition, but the long term neurobehavioral consequences may be similar. Maciag D, Coppinger D, Paul IA (December 2006). “Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development”. Brain Res. 1125 (1): 171–5. doi:10.1016/j.brainres.2006.10.009. PMC 1762094. PMID 17101120. Short-term effects There are physiological changes while on SSRIs. It has been postulated that drugs can exert epigenetic effects. Csoka AB, Szyf M (November 2009). “Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology”. Med. Hypotheses 73 (5): 770–80. doi:10.1016/j.mehy.2008.10.039. PMID 19501473. Changes include reduced hypothalamic-pituitary-testis axis (HPTA) function, Safarinejad MR (August 2008). “Evaluation of endocrine profile and hypothalamic-pituitary-testis axis in selective serotonin reuptake inhibitor-induced male sexual dysfunction”. J Clin Psychopharmacol 28 (4): 418–23. doi:10.1097/JCP.0b013e31817e6f80. PMID 18626269. decreased testosterone levels, Cohen AJ. Antidepressant-Induced Sexual Dysfunction Associated with Low Serum Free Testosterone. Psychiatry Online 1999. reduced sperm counts, which showed marked improvement after discontinuation Tanrikut C, Schlegel PN (January 2007). “Antidepressant-associated changes in semen parameters”. Urology 69 (1): 185.e5–7. doi:10.1016/j.urology.2006.10.034. PMID 17270655. and reduced semen quality with damaged sperm DNA, which is reversible after discontinuation. Safarinejad MR (November 2008). “Sperm DNA damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay”. J. Urol. 180 (5): 2124–8. doi:10.1016/j.juro.2008.07.034. PMID 18804223. Long-term effects Treatment with fluoxetine (Prozac) has been shown to cause persistent desensitization of 5HT1A receptors after removal of the SSRI in rats. Raap DK, Garcia F, Muma NA, Wolf WA, Battaglia G, van de Kar LD (February 1999). “Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z proteins”. J. Pharmacol. Exp. Ther. 288 (2): 561–7. PMID 9918559. These long-term adaptive changes in 5-HT receptors, as well as more complex, global changes, are thought to be mediated through alterations of gene expression. Faure C, Mnie-Filali O, Haddjeri N (February 2006). “Long-term adaptive changes induced by serotonergic antidepressant drugs”. Expert Rev Neurother 6 (2): 235–45. doi:10.1586/14737175.6.2.235. PMID 16466303. Palotás M, Palotás A, Puskás LG, et al. (December 2004). “Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram”. Int. J. Neuropsychopharmacol. 7(4): 401–13. 10.1017/S1461145704004493. PMID 15315716. Kálmán J, Palotás A, Juhász A, et al. (November 2005). “Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression–evolution of antidepressants and the role of the “neuro-immune” system”. Neurochem. Res. 30 (11): 1429–38. doi:10.1007/s11064-005-8513-9. PMID 16341940. Yamada M, Yamada M, Higuchi T (July 2005). “Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy”. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (6): 999–1009. doi:10.1016/j.pnpbp.2005.03.022. PMID 15975701. Boehm C, Newrzella D, Herberger S, Schramm N, Eisenhardt G, Schenk V, Sonntag-Buck V, Sorgenfrei O (2006). “Effects of antidepressant treatment on gene expression profile in mouse brain: cell type-specific transcription profiling using laser microdissection and microarray analysis”. J Neurochem. 97 (Suppl 1): 44–9. doi:10.1111/j.1471-4159.2006.03750.x. PMID 16635249. Some of these gene expression changes are a result of altered DNA structure caused by chromatin remodeling, Hyman SE (April 2006). “Even chromatin gets the blues”. Nat. Neurosci. 9 (4): 465–6. doi:10.1038/nn0406-465. PMID 16568101. Newton SS, Duman RS (August 2006). “Chromatin remodeling: a novel mechanism of psychotropic drug action”. Mol. Pharmacol. 70 (2): 440–3. doi:10.1124/mol.106.027078. PMID 16728645. specifically epigenetic modification of histones Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (April 2006). “Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action”. Nat. Neurosci. 9 (4): 519–25. doi:10.1038/nn1659. PMID 16501568. and gene silencing by DNA methylation due to increased expression of the methyl binding proteins MeCP2 and MBD1. Cassel S, Carouge D, Gensburger C, et al. (August 2006). “Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain”. Mol. Pharmacol. 70 (2): 487–92. doi:10.1124/mol.106.022301. PMID 16670375. Altered gene expression and chromatin remodeling may also be involved in the mechanism of action of electroconvulsive therapy (ECT). Altar CA, Laeng P, Jurata LW, et al. (March 2004). “Electroconvulsive seizures regulate gene expression of distinct neurotrophic signaling pathways”. J. Neurosci. 24 (11): 2667–77. doi:10.1523/JNEUROSCI.5377-03.2004. PMID 15028759. Tsankova NM, Kumar A, Nestler EJ (June 2004). “Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures”. J. Neurosci. 24 (24): 5603–10. doi:10.1523/JNEUROSCI.0589-04.2004. PMID 15201333. Because described gene expression changes are complex, and can involve persistent modifications of chromatin structure, it has been suggested that SSRI use can result in persistently altered cerebral gene expression leading to compromised catecholaminergic neurotransmission and neuroendocrine disturbances. However, without detailed neuropsychopharmacological, pharmacogenomic and toxicogenomic Szyf M (2004). “Toward a Discipline of Pharmacoepigenomics”. Current Pharmacogenomics 2(4): 357–377. doi:10.2174/1570160043377358. research, the definitive cause remains unknown. Relationship to “chemical imbalance” theory Some critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do. Lacasse JR, Leo J (December 2005). “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature”. PLoS Med. 2 (12): e392. doi:10.1371/journal.pmed.0020392. PMC 1277931. PMID 16268734. Much of the criticism stems from questions about the validity of claims that SSRIs work by correcting chemical imbalances. Without tools to accurately measure neurotransmitter levels and to allow for continuous monitoring during treatment, it remains difficult to know if one is correctly targeting a deficient neurotransmitter (i.e. correcting an imbalance) or reaching a desirable level of a particular neurotransmitter. It has been argued that without this knowledge for each patient, SSRIs can actually cause chemical imbalances and abnormal brain states. Moncrieff J, Cohen D (July 2006). “Do Antidepressants Cure or Create Abnormal Brain States?”. PLoS Med. 3 (7): e240. doi:10.1371/journal.pmed.0030240. PMC 1472553. PMID 16724872. One possible mechanism is by inhibition of dopaminergic neurotransmission, Damsa C, Bumb A, Bianchi-Demicheli F, et al. (August 2004). “Dopamine-dependent” side effects of selective serotonin reuptake inhibitors: a clinical review”. J Clin Psychiatry 65 (8): 1064–8. doi:10.4088/JCP.v65n0806. PMID 15323590. resulting in described persistent sexual dysfunction. Other drugs Antipsychotics are also known to cause sexual dysfunction that is similar to PSSD, especially because of their antagonist effects on D2 dopamine receptors, as well as H1, α1 and α2 antagonism. “Side effects of atypical antipsychotics: a brief overview”. Finasteride, which is used to treat male pattern baldness and benign prostatic hypertrophy, has also been found to cause persistent sexual dysfunction in a subset of patients that are treated with the drug. http://abcnews.go.com/Health/ + baldness-drug-propecia-long-lasting-possibly-permanent-sexual/story?id=16758123#.UCecOGlrPww/ Treatment There is no known cure for PSSD, mostly because its etiology is still poorly understood. Possible treatment options for SSRI-induced sexual dysfunction have been reviewed theoretically. Keller Ashton A, Hamer R, Rosen RC (1997). “Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients”. J Sex Marital Ther 23 (3): 165–75. doi:10.1080/00926239708403922. PMID 9292832. Keltner NL, McAfee KM, Taylor CL (2002). “Mechanisms and treatments of SSRI-induced sexual dysfunction”. Perspect Psychiatr Care 38 (3): 111–6. doi:10.1111/j.1744-6163.2002.tb00665.x. PMID 12385082. Sukoff Rizzo SJ, Pulicicchio C, Malberg JE, et al. (September 2009). “5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats”. Int. J. Neuropsychopharmacol. 12 (8): 1045–53. doi:10.1017/S1461145709000406. PMID 19435548. However, there has been a lack of randomized, placebo-controlled, double-blind trials of potential treatments. Of those that have been done, there is evidence for the following management strategies: for erectile dysfunction, the addition of a PDE5 inhibitor such as sildenafil; for decreased libido, possibly adding or switching to Wellbutrin (Bupropion); and for overall sexual dysfunction, switching to nefazodone. Balon R (2006). “SSRI-Associated Sexual Dysfunction”. The American Journal of Psychiatry 163(9). According to a survey of psychiatrists, Bupropion is the drug of choice for the treatment of SSRI-induced sexual dysfunction, although this is not an FDA-approved indication. Thirty-six percent of psychiatrists preferred switching patients with SSRI-induced sexual dysfunction to bupropion, and 43 percent favored the augmentation of the current medication with bupropion. Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J, Nierenberg AA, Rosenbaum JE, Fava M. (2002). “The pharmacologic management of SSRI-induced side effects: a survey of psychiatrists”. Ann Clin Psychiatry 14 (3): 143–7. doi:10.3109/10401230209147450. PMID 12585563. A higher dose of bupropion (minimum 300 mg) may be necessary: a randomized study with 31 subjects that utilized a lower dose (150 mg) once daily failed to find a significant difference between bupropion, sexual therapy or combined treatment, Cabello F (February 2006). “Effectiveness of the Treatment of Female Hypoactive Sexual Desire Disorder”. J Sex Res. Retrieved 2007-04-05. while a subsequent study with 234 subjects and employing Bupropion SR 150 mg twice daily did show a significant improvement of sexual function. Safarinejad M (September 2010). “The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study”. BJU International. Some other off-label prescriptions include pramipexole, ropinirole, yohimbine and possibly other molecules increasing the dopamine blood levels, though there have been no double blind placebo-controlled trials to show their efficacy. The chemical cabergoline, which is an agonist of D2 receptors, which in turn decreases prolactin, has fully restored orgasm in 1/3rd of anorgasmic subjects, and partially restored orgasm in another 1/3rd of subjects. http://www.everydayhealth.com/sexual-health/0524/drug-restores-normal-orgasm-in-men.aspx Most studies of sexual dysfunction have been done in men, though some studies done in women have shown benefit from bupropion (at doses >300 mg/d). There has been 1 study showing possible benefit in orgasmic function with sildanefil, though no change in desire or arousal. Burghardt K (2013). “Sildenafil for SSRI-induced sexual dysfunction in women”. Current Psychiatry. Controversy This article was taken down on 27th January 2014. One of the reasons for removal was supposedly the lack of peer-reviewed published research on the issue. RxISK.org “Post-SSRI Sexual Dysfunction: Wikipedia Falls”. The publication of a 120 person case series remedies this. Hogan C, Le Noury J, Healy D, Mangin D (2014). “One hundred and twenty cases of enduring sexual dysfunction following treatment”. Int J Risk Saf Med 26 (2): 109-16. doi:10.3233/JRS-140617. PMID 24902508. This publication outlines a degree of overlap between post-finasteride syndrome (PFS), post-isotretinoin syndrome and PSSD. These links may offer insights on what might be causing the problem. http://wp.rxisk.org/wikipedia-editor-inserts-foot-in-mouth/ References Category:Sexual arousal Category:Mammal reproductive system Category:Sexual disorders Category:Selective serotonin reuptake inhibitors